Many Veterans experience occupational exposure to low-level blast (LLB) during normal training operations, including but not limited to breaching activity. These Veterans are at increased risk for persisting neuropsychological impairment due to repeated LLB exposure over several deployments with limited time for recovery between exposures. The extent of the long-term consequences after cumulative LLB exposure is unknown, though reports show that deficits can be present late in life. Furthermore, the resultant post-traumatic stress disorder (PTSD)-related behavioral deficits are more pronounced in soldiers and Veterans with a history of chronic blast exposure. There is no clear understanding of which pathological mechanisms drive this chronic PTSD phenotype after LLB exposure. A few animal models have been established to address this incomplete understanding of the pathobiological mechanisms underlying LLB exposure. These models replicate the chronic depressive, anxiogenic, and PTSD-related traits observed in Veterans, though there are many knowledge gaps in what contributes to these chronic deficits. In general, blast exposure causes acute blood- brain barrier (BBB) and neurovascular unit abnormalities that can persist over time. The overall objective of this application is to determine the timing of acute neurovascular dysfunction after LLB and how repeating LLB contributes to chronic neurovascular impairment and neuropsychological deficits. Our central hypothesis is that LLB repeated at a time interval of maximal BBB impairment, after the first LLB, will result in persistent PTSD- like behavioral traits. Additionally, these deficits will be associated with changes in the profile of serum-derived exosomal miRNAs and platelet bioenergetics. These hypotheses were formulated based on current literature and our own published and preliminary data demonstrating anxiety and amygdalar BBB disruption after blast exposure. By utilizing a multimodal blast simulator at the University of Kentucky, these studies will be able to examine the longitudinal behavioral profile, coupled with pathologically relevant biomarkers. These hypotheses will be tested in three specific aims: 1) examine acute neurovascular deficits after a single LLB exposure and determine their relationship to longitudinal behavioral traits, 2) determine how repeating LLB at various time intervals, based on the acute neurovascular profile, contributes to exacerbated or prolonged PTSD-like behavioral traits and chronic neurovascular impairment, 3) identify if modulating either acute or chronic neurovascular health using sildenafil will mitigate long-term PTSD-like behavioral traits. This research will drastically improve our understanding of the effects of LLB as well as potentially identify novel, clinically- relevant biomarkers. The proposed research is significant because it will establish a platform to understand the chronic effects of occupational blast exposure, which affects many Veterans. In addition, this line of investigation can lead to better therapeutic targeting of neurovascular dysfunction to improve neurological outcome in aging Veterans. In addition to the research products gained by this proposal, the applicant will greatly benefit from a mentoring team that has a variety of preclinical, translational, and clinical perspectives, which will contribute to a well-rounded career development plan. The training program will add additional techniques to Dr. Hubbard?s? repertoire, contributing not only to this proposal but to his VA research program moving forward. With prior knowledge in blast injury modeling, additional behavioral and biomarker assays will greatly advance his research expertise. In the latter years of this proposal, Dr. Hubbard will continue to expand grant writing, student mentoring, collaborative research and presentation skills required of independent researchers. Overall, the proposed studies and diverse mentoring program will culminate in producing a highly successful independent VA researcher.